Summary Obesity has become a global epidemic and greatly increases the risk for diabetes, cardiovascular disease, and non-alcoholic fatty liver disease (NAFLD). Nearly 80% of obese people develop NAFLD, which progresses to steatohepatitis (NASH) and further to end-stage liver diseases, such as fibrosis, cirrhosis, and liver cancer, but good therapeutic options to treat NAFLD are not available. The hallmark of NAFLD is abnormal accumulation of triglyceride (TG) in the liver due to dysregulated lipid metabolism. Bile acids (BAs) are recently recognized signaling molecules that profoundly impact metabolism and counteract obesity. The BA-induced intestinal hormone, FGF15/19 (mFGF15. hFGF19), has received great attention because its lipid-lowering and insulin-sensitizing effects and, thus, its therapeutic potential in treating obesity and diabetes. However, little is known about how FGF15/19 controls lipid metabolism. The overall goal of this application is to determine how an orphan nuclear receptor Small Heterodimer Partner (SHP, NR0B2) mediates postprandial actions of FGF15/19 by epigenetic regulation of hepatic lipid metabolism. We have preliminary data showing that FGF19 treatment induced recruitment of DNA methyltransferase-3a (DNMT3a) to key lipogenic genes in a SHP-dependent manner, and liver-specific downregulation of SHP or DNMT3a led to decreased 5-methyl cytosine (5mC) DNA levels at these genes and increased liver TG levels, suggesting a novel function of SHP and DNMT3a in hepatic lipogenesis. Based these exciting preliminary data, we hypothesize that SHP physiologically mediates epigenetic repression of hepatic lipogenesis by recruiting DNMT3a, in response to FGF15 signaling in the late fed-state, but this FGF15- SHP-DNMT3a regulatory axis is disrupted in obesity. To test this hypothesis, we will 1) determine the role and the underlying mechanisms of how the FGF15-SHP-DNMT3a regulatory axis mediates epigenetic repression of hepatic lipogenic genes, and then, 2) investigate the in vivo function of hepatic SHP and DNMT3a in regulation of liver lipid metabolism, focusing on de novo lipogenesis, and dysregulation of this regulatory axis in obesity in mice and determine human relevance by analysis of liver samples from NAFLD patients. To achieve these goals, multifaceted approaches, including molecular/biochemical, metabolic, and epigenetic studies and global genomic analyses, will be utilized in SHP-LKO and FGF15-KO mice, and mouse models generated by viral-mediated expression and downregulation of proteins. Impact: Our expertise on transcriptional and epigenetic control of liver lipid metabolism by nuclear receptors uniquely qualifies us to carry out this project. This proposal will test whether SHP and DNMT3a mediate FGF15/19 actions in hepatic lipid metabolism, and may reveal effective approaches for developing new therapeutic targets for NAFLD and diagnostic biomarkers to monitor its progression.